Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in the United States. Among all EOC subtypes, ovarian clear cell carcinoma (OCCC) carries the worst prognosis when diagnosed at an advanced stage and there is currently no effective therapy for this disease. ARID1A, a subunit of the epigenetic SWI/SNF chromatin remodeler, is among the genes that show the highest mutation rates across many cancer types. In fact, the ARID1A gene is the highest mutated gene in OCCC that occurs in over 50% of the cases. The ultimate goal of the current proposal is to develop novel approaches to treat and eradicate this devastating disease. Since ARID1A is the highest mutated gene in OCCC, we performed an unbiased screen and demonstrated that in ARID1A mutated OCCC the inhibition of EZH2, another epigenetic regulator, is synthetically lethal. The observed synthetic lethality is due to antagonistic roles played by ARID1A and EZH2 in regulating the expression of the same set of target genes. Inhibition of PI3K/AKT signaling contributes to the observed synthetic lethality. Interestingly, ARID1A mutation typically co-exists with PIK3CA mutation in OCCC. In addition to EZH2, our unexplored data suggest that ARID1A-mutated OCCC cells are also selectively sensitive to inhibition of HDAC2. ARID1A mutation is mutually exclusive from TP53 mutation, and expression of p53 target genes is impaired by ARID1A mutation. However, the mechanism by which ARID1A regulates p53 activity has never been explored. Our preliminary data indicate that ARID1A mutation correlates with the association of myosin IIa (MyoIIa) with the SWI/SNF complex in an ARID1A status-dependent manner. MyoIIa is a known tumor suppressor that is necessary for p53 activity. Thus, these studies suggest that ARID1A mutation impairs p53 activity through MyoIIa sequestration. Our central hypothesis is that ARID1A-mutated OCCC can be treated and ultimately eradicated by targeting the four proteins (namely EZH2, HDAC2, PI3K and p53) we have implicated. Accordingly, three specific aims are proposed: Aim 1: To investigate the role of HDAC2 in the observed synthetic lethality and gene expression antagonism between ARID1A and EZH2; Aim 2. To investigate the mechanisms by which ARID1A regulates p53 activity through MyoIIa; and Aim 3. To develop novel therapeutic strategies for ARID1A mutation. The proposed studies are highly innovative because they challenge current research/clinical paradigms, contribute to new concepts for epigenetic therapeutics, and utilize innovative methods to explore new intervention strategies for ARID1A-mutated OCCC. The research proposed is of high impact because it has the potential to establish the first effective targeted therapeutic strategy for OCCC. Since genetic alterations in components of the SWI/SNF chromatin-remodeling complex occur in more than 20% of all human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.